Cistanche deserticola extract and its active components, echinacoside, ameliorate sarcopenia by activating the IGF-1/PI3K-AKT pathway to modulate ferroptosis

  • Phytomedicine. 2025 Oct 5:148:157378. doi: 10.1016/j.phymed.2025.157378.
Xiaomin Wang  1 ,  Liping Zhu  2 ,  Ruoyutong Du  2 ,  Ang Li  1 ,  Na Li  1 ,  Xiaoying Liu  3 ,  Yin Zhang  2 ,  Xiaoqin Liu  2 ,  Qiong Wang  2 ,  Chao Han  4 ,  Chao Qu  5 ,  Wei Zou  4 ,  Jing Liu  6 ,  Yanfu Wang  7
Affiliations
  • 1. Department of General Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China; Dalian Medical University, Dalian, Liaoning, China.
  • 2. Department of Gerontology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China; Dalian Medical University, Dalian, Liaoning, China.
  • 3. Department of General Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
  • 4. Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China; Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning, China.
  • 5. Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, China.
  • 6. Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China; Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning, China. Electronic address: [email protected].
  • 7. Department of General Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China; Department of Gerontology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China. Electronic address: [email protected].
PMID: 41106096 DOI: 10.1016/j.phymed.2025.157378
Abstract

Background: Sarcopenia (SP) is characterized by progressive loss of skeletal muscle mass and function, and is a significant health burden in an aging society. Existing therapies have limited effectiveness. While Ferroptosis plays a key role in sarcopenia, its regulatory mechanism remains unclear. As a traditional tonifying Chinese medicine, Cistanche deserticola has antioxidant potential due to its active ingredient, echinacoside (ECH); however, its mechanism of action in sarcopenia remains to be elucidated.

Purpose: To investigate the effects of Cistanche deserticola extract (CDE) and ECH on improving sarcopenia, with a focus on elucidating their molecular mechanisms of inhibiting Ferroptosis in C2C12 cells by regulating the IGF-1/PI3K-AKT pathway.

Methods: HPLC/MS was used to quantify the ECH content in CDE; Predicting common targets of ECH and sarcopenia through network pharmacology and verifying binding ability through molecular docking; Construct an in vitro model of muscle atrophy induced by dexamethasone (DEX) and intervene with CDE and low/high concentrations of ECH (l-ECH/H-ECH) to detect cell viability, Ferroptosis markers, and pathway molecules; Establish a sarcopenia mouse model in vivo to evaluate skeletal muscle mass, function, and molecular changes; Combining untargeted metabolomics to analyze muscle metabolic profiles.

Results: HPLC/MS showed that the ECH content in CDE was 43.15 ± 0.2 mg/g. Network pharmacology analysis revealed that ECH shares 217 core targets with sarcopenia, significantly enriched in the IGF-1/PI3K-AKT pathway and Ferroptosis regulation. In vitro, CDE and ECH inhibited dexamethasone-induced myotube atrophy in a concentration-dependent manner, and H-ECH effectively replaced CDE; Simultaneously inhibiting Ferroptosis and improving mitochondrial function. In vivo, H-ECH significantly increased muscle fiber cross-sectional area, grip strength, and endurance, and activated the IGF-1/PI3K-AKT pathway to downregulate ferroptosis-promoting genes. Non-targeted metabolomics showed that ECH reversed dexamethasone-induced energy metabolism disorders and ferroptosis-related metabolite (arachidonic acid and glutathione) imbalance, and enriched pathways such as glutathione and arachidonic acid metabolism. PI3K inhibitors blocked the protective effects of ECH.

Conclusions: ECH, the main active ingredient of Cistanche deserticola, inhibits Ferroptosis in C2C12 cells and reverses skeletal muscle atrophy through concentration-dependent activation of the IGF-1/PI3K-AKT pathway. This study provides new targets and experimental evidence for the treatment of sarcopenia with traditional Chinese medicine.

Keywords
Echinacoside(ECH); Ferroptosis; IGF-1/PI3K-AKT signaling pathway; Metabolomics; sarcopenia.
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